ProjectDefining the role of Arp2/3 complex diversity at multiple scales of biology

Researcher (PI)Michael WAY

Host Institution (HI)THE FRANCIS CRICK INSTITUTE LIMITED

Call DetailsSynergy Grants (SyG), SyG3LSa, ERC-2018-SyG

SummaryThe actin cytoskeleton of the cell is critical for the complex, integrated processes associated with development, operation and sustainability of the human body. The Arp2/3 complex consisting of seven protein subunits is essential to stimulate dynamic branched actin networks needed for multiple cellular processes. The Arp2/3 complex has always been considered as a single entity, but in humans and other mammals, three of the Arp2/3 complex subunits are encoded by two isoforms, thus allowing the formation of eight distinct Arp2/3 complexes. The Way lab has shown that Arp2/3 subunit composition dramatically affects the formation and stability of branched actin networks. The Way and Gomes labs have shown how specific Arp2/3 isoforms are essential for muscle development.
Our synergistic, high-risk, high-gain goal is to define the role of Arp2/3 complex diversity at three hierarchies of biology:
1. Molecular basis of Arp2/3 diversification
With purified isoform-specific complexes we will perform cryo-electron microscopy and single molecule fluorescence microscopy to reveal the structural variations and influence of Arp2/3 diversity on actin networks in vitro.
2. Cellular function of different Arp2/3 complexes
With cells expressing specific Arp2/3 isoforms, we will use quantitative live cell imaging and cryoelectron tomography to reveal the dependence of cellular actin networks on Arp2/3 diversity and its functional consequences.
3. Developmental and physiological role of individual Arp2/3 complexes.
With genetically modified cultured myofibers and transgenic mice, we will use an array of imaging approaches to reveal the contribution of different Arp2/3 family members to muscle development, structure and physiology.
Our interdisciplinary plan builds on the strengths of our three labs, takes advantage of unique reagents and powerful model systems, and will allow us to determine how Arp2/3 diversity contributes to biological complexity at multiple scales.

The actin cytoskeleton of the cell is critical for the complex, integrated processes associated with development, operation and sustainability of the human body. The Arp2/3 complex consisting of seven protein subunits is essential to stimulate dynamic branched actin networks needed for multiple cellular processes. The Arp2/3 complex has always been considered as a single entity, but in humans and other mammals, three of the Arp2/3 complex subunits are encoded by two isoforms, thus allowing the formation of eight distinct Arp2/3 complexes. The Way lab has shown that Arp2/3 subunit composition dramatically affects the formation and stability of branched actin networks. The Way and Gomes labs have shown how specific Arp2/3 isoforms are essential for muscle development.
Our synergistic, high-risk, high-gain goal is to define the role of Arp2/3 complex diversity at three hierarchies of biology:
1. Molecular basis of Arp2/3 diversification
With purified isoform-specific complexes we will perform cryo-electron microscopy and single molecule fluorescence microscopy to reveal the structural variations and influence of Arp2/3 diversity on actin networks in vitro.
2. Cellular function of different Arp2/3 complexes
With cells expressing specific Arp2/3 isoforms, we will use quantitative live cell imaging and cryoelectron tomography to reveal the dependence of cellular actin networks on Arp2/3 diversity and its functional consequences.
3. Developmental and physiological role of individual Arp2/3 complexes.
With genetically modified cultured myofibers and transgenic mice, we will use an array of imaging approaches to reveal the contribution of different Arp2/3 family members to muscle development, structure and physiology.
Our interdisciplinary plan builds on the strengths of our three labs, takes advantage of unique reagents and powerful model systems, and will allow us to determine how Arp2/3 diversity contributes to biological complexity at multiple scales.

Max ERC Funding

10 715 153 €

Duration

Start date: 2019-07-01, End date: 2025-06-30

Project acronymNatural BionicS

ProjectNatural Integration of Bionic Limbs via Spinal Interfacing

Researcher (PI)Dario FARINA

Host Institution (HI)IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE

Call DetailsSynergy Grants (SyG), SyG3PEb, ERC-2018-SyG

SummaryMissing a limb leads to dramatic impairments in the capacity to move and interact with the environment and to a substantial worsening in quality of life. This deficiency is also associated with a large portion of the sensory-motor cortex facing neural deafness. Missing or damaged limbs can in principle be substituted by robotic limbs, connected to humans with neural interfacing. Despite massive research efforts, however, the bionic reconstruction of limbs currently faces important translational challenges. We aim at filling this gap between academic research and clinical impact with a patient-centric approach that synergistically combines breakthroughs in surgery (Aszmann), neural interfacing (Farina), and robotics (Bicchi). We propose to surgically create bio-connectors (compacted in a bio-hub) to access the spinal cord circuitries by using biological pathways of encoding and decoding neural information. Neural interfacing with the bio-hub will determine an input/output information flow with the spinal cord by decoding the activity of spinal neural cells (output) and stimulating transplanted biological afferent organs (input). The sensory-motor image of the missing limb emerging from this interfacing will be projected in soft robotic arms/legs that will embed kinematic synergies and tactile-proprioceptive functions, intimately matched with the neural sensory-motor synergies extracted from the bio-hub. In this way, Natural BionicS aims at creating a fully integrated, symbiotic replacement of human limbs with robotic parts that the user will feel and command as part of the body. This aim will be achieved with clinical translation aided by the establishment of a Bionic Clinical Board of the three PIs. Here the options of bionic reconstruction will be explored for each patient on a bi-monthly basis, the engineering solutions will be adapted to the clinical challenges, and patients will be identified who best profit from the radical new developments of Natural BionicS.

Missing a limb leads to dramatic impairments in the capacity to move and interact with the environment and to a substantial worsening in quality of life. This deficiency is also associated with a large portion of the sensory-motor cortex facing neural deafness. Missing or damaged limbs can in principle be substituted by robotic limbs, connected to humans with neural interfacing. Despite massive research efforts, however, the bionic reconstruction of limbs currently faces important translational challenges. We aim at filling this gap between academic research and clinical impact with a patient-centric approach that synergistically combines breakthroughs in surgery (Aszmann), neural interfacing (Farina), and robotics (Bicchi). We propose to surgically create bio-connectors (compacted in a bio-hub) to access the spinal cord circuitries by using biological pathways of encoding and decoding neural information. Neural interfacing with the bio-hub will determine an input/output information flow with the spinal cord by decoding the activity of spinal neural cells (output) and stimulating transplanted biological afferent organs (input). The sensory-motor image of the missing limb emerging from this interfacing will be projected in soft robotic arms/legs that will embed kinematic synergies and tactile-proprioceptive functions, intimately matched with the neural sensory-motor synergies extracted from the bio-hub. In this way, Natural BionicS aims at creating a fully integrated, symbiotic replacement of human limbs with robotic parts that the user will feel and command as part of the body. This aim will be achieved with clinical translation aided by the establishment of a Bionic Clinical Board of the three PIs. Here the options of bionic reconstruction will be explored for each patient on a bi-monthly basis, the engineering solutions will be adapted to the clinical challenges, and patients will be identified who best profit from the radical new developments of Natural BionicS.

Max ERC Funding

9 984 021 €

Duration

Start date: 2019-06-01, End date: 2025-05-31

Project acronymQuantumBirds

ProjectRadical pair-based magnetic sensing in migratory birds

Researcher (PI)Peter HORE

Host Institution (HI)THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD

Call DetailsSynergy Grants (SyG), SyG3PEb, ERC-2018-SyG

SummaryThe navigational and sensory abilities of night-migratory songbirds, travelling alone over thousands of kilometres, are absolutely staggering. The successful completion of these magnificent voyages depends crucially on the birds’ ability to sense the Earth’s magnetic field. Exactly how this magnetic sense works is one of the most significant open questions in biology and biophysics. The experimental evidence suggests something extraordinary. The birds’ magnetic compass sensor seems to rely on coherent quantum phenomena that indirectly allow magnetic interactions a million times smaller than kBT (Boltzmann’s constant multiplied by temperature) to be detected in biological tissue. QuantumBirds brings together quantum physics, spin chemistry, behavioural biology, biochemistry, and molecular biology in a unique, ambitious, imaginative and genuinely synergetic research programme that will prove whether the primary magnetic detection event occurring in the birds’ retinas involves the quantum spin dynamics of photochemically formed radical pairs in cryptochrome proteins.
We will address three specific questions:
1. Are avian cryptochromes capable of functioning as magnetic compass receptors?
2. Do retinal neurons encode light-dependent, cryptochrome-derived magnetic information?
3. Are cryptochromes the primary magnetoreceptor molecules for magnetic compass orientation?
Success in this endeavour will: (a) revolutionise our understanding of magnetoreception, the least understood of all biological senses; (b) firmly establish the emerging field of “Quantum Biology” and thereby reduce by six orders of magnitude the threshold for sensory detection of weak stimuli in biological systems; (c) prepare the ground for the development of a novel and powerful range of bio-inspired magnetic sensing devices; and (d) provide insights that could be applied in quantum computing and guide research into the potential effects of weak anthropogenic electromagnetic fields on human health.

The navigational and sensory abilities of night-migratory songbirds, travelling alone over thousands of kilometres, are absolutely staggering. The successful completion of these magnificent voyages depends crucially on the birds’ ability to sense the Earth’s magnetic field. Exactly how this magnetic sense works is one of the most significant open questions in biology and biophysics. The experimental evidence suggests something extraordinary. The birds’ magnetic compass sensor seems to rely on coherent quantum phenomena that indirectly allow magnetic interactions a million times smaller than kBT (Boltzmann’s constant multiplied by temperature) to be detected in biological tissue. QuantumBirds brings together quantum physics, spin chemistry, behavioural biology, biochemistry, and molecular biology in a unique, ambitious, imaginative and genuinely synergetic research programme that will prove whether the primary magnetic detection event occurring in the birds’ retinas involves the quantum spin dynamics of photochemically formed radical pairs in cryptochrome proteins.
We will address three specific questions:
1. Are avian cryptochromes capable of functioning as magnetic compass receptors?
2. Do retinal neurons encode light-dependent, cryptochrome-derived magnetic information?
3. Are cryptochromes the primary magnetoreceptor molecules for magnetic compass orientation?
Success in this endeavour will: (a) revolutionise our understanding of magnetoreception, the least understood of all biological senses; (b) firmly establish the emerging field of “Quantum Biology” and thereby reduce by six orders of magnitude the threshold for sensory detection of weak stimuli in biological systems; (c) prepare the ground for the development of a novel and powerful range of bio-inspired magnetic sensing devices; and (d) provide insights that could be applied in quantum computing and guide research into the potential effects of weak anthropogenic electromagnetic fields on human health.